Syringomyelia: Discovery of cause of syringomyelia, a form of progressive paralysis affecting the spinal cord, should result in less invasive and more effective treatment. Syringomyelia, a cyst in the spinal cord, causes progressive paralysis in affected patients, including patients in childhood and early adulthood. Because the mechanism underlying the development and progression of syringomyelia has been unknown, there are a variety of current therapies, including surgery to open the spinal cord and the placement of drainage systems into the spinal cord. Understanding the mechanism causing syringomyelia may permit the identification of treatment that is more effective and less invasive. The purpose of this study is to establish the mechanism(s) of the progression of syringomyelia associated with abnormalities at the craniocervical junction. A clinical study elucidating the basis of syringomyelia was recently completed in which the mechanism was shown, paradoxically, to be one that is outside the spinal cord by the following mechanism. The cerebellar tonsils and the brainstem act on a partially enclosed spinal subarachnoid space to generate cervical subarachnoid CSF pressure waves. These waves compress the spinal cord from without, not from within, as had previously been considered to occur, to propel the syrinx fluid downward with each heartbeat. Syrinx progression occurs as a consequence. Craniocervical decompression and duraplasty improved CSF flow at the foramen magnum in all patients. This, along with other observations made in the same study, indicated that successful treatment should not require entering the spinal cord al all. Successful surgery, by a procedure that does not invade the nervous system, eliminated the anatomic cause of the excess pressure waves and resulted in consistent resolution of syringomyelia. The demonstration of this mechanism should result in less invasive surgery and more effective treatment for this form of progressive paralysis. Clinical and laboratory investigation of central nervous system vascular disorders: Delayed cerebral vasospasm is the most common cause of death or disability in patients with subarachnoid hemorrhage who survive to reach the hospital. We have investigated the mechanism of delayed vasospasm and examined new approaches for therapy of it. In a series of experiments, we have shown that two new approaches, a ferrous iron chelator and intracarotid infusion of a nitric oxide (NO) donor, reverse and prevent vasospasm after subarachnoid hemorrhage in primates. The intracarotid route of NO donor delivery was chosen after success with ICA delivery, but failure of intravenous infusion, of the NO donor to reverse or prevent vasospasm in primates. We are preparing a pilot clinical study of intracarotid infusion of the NO donor in humans for reversal/prevention of cerebral vasospasm after rupture of an aneurysm.To further the understanding of vasospasm, as well as to develop new strategies for its treatment, we are studying the influence of different compounds on CBF, cerebral vessel diameter, and on NO/cGMP production in a series of in vivo experiments using a laser Doppler probe for CBF measurement, an NO in vivo probe, and TCD. With the use of thrombolytic therapy for ischemic stroke, reperfusion injury has become an important issue, as it appears to underly the risks associated with delayed treatment. We have shown that an intracarotid infusion of ProliNO (a Nitric Oxide donor) a) quenches oxygen free radical production and b) reduces the volume of brain infarction in a rat model of global transient cerebral ischemia. We continue experiments with the use of ProliNO in two different models of transient ischemia: a rat middle cerebral artery transient occlusion model and a rabbit embolism model. The hypothesis for these experiments is that the limited efficacy of r-tPA used in humans for treatment of ischemic stroke is due to damage generated upon brain reperfusion, and it is primarily mediated by oxygen free radical generation. In acute experiments with the rat model, we observed a significant decrease of stroke volume by intracarotid infusion of proliNO. This effect was comparable to the use of a new oxygen free radical scavenger (stable nitroxide, Tempol). In the rabbit model, we observed a decrease of oxygen free radical levels in response to intracarotid infusion of proliNO at the time of r-tPA-related reperfusion. We continue to study influences of the NO donor and stable nitroxide (a new compound that does not produce hypotension) in the in vivo chronic experiments to assess the long-term outcome of this treatment.Depending on concentration, nitric oxide (NO), due to its chemical properties, modulates different enzymatic pathways. It has been described as inducing cell death, or stimulating endothelial cell proliferation during angiogenesis. In a series of in vitro experiments using cell cultures, aortic rings, and different NO donors we observed dose-dependent opposite effects on angiogenesis. We concluded that NO, depending on concentration, produces either endothelial cell proliferation or inhibition of growth. These observations suggest a role for NO in control of angiogenesis and a possible therapeutic use of NO donors for control of tumor growth. Temporary vascular occlusion is an important part of neurosurgery, but the capacity to monitor the effects of occlusion in real time has been limited. In circumstances that require temporary vascular occlusion during surgery (aneurysms, AVMs, tumors, etc.), the ability to visualize flow in the vessels and their distribution bed would be beneficial. During the use of a sensitive (0.02 dagC), high-resolution (up to 50mm), and rapid (up to 2msec/frame) infrared camera for localizing cortical function during surgery, we observed imaging of the cerebral arteries and veins with striking resolution. This approach for detecting sudden changes in blood flow in cerebral vessels and brain is being examined in primates and humans. The functional status of the globus pallidus internal segment (Gpi) plays a key role in mediating the effects of antiparkinsonian drugs. The mechanism by which providing dopamine to a denervated striatum produces abnormal movements along with the expected reversal of parkinsonian features remains unknown. To address this issue we used single cell recording of the firing of GPi cells in 1-methyl-4-phenyl- 1,2,3,6- tetrahydropyridine (MPTP)-parkinsonian monkeys that developed dyskinesias after chronic levodopa treatment. The transition from the 'off' to the 'on' state was characterized by a decrease (most cells), no change, or an increase in firing rate of individual cells. During dyskinesias firing rates fell profoundly in almost all cells, with decrements as low as 97% in individual cells. These changes occurred only when dyskinesias were present. To avoid the risks associated with pooling activity from different functional groups of cells in the different states, we recorded single cells in the GPi of parkinsonian monkeys continuously through the 'off' and 'on' states, and 10- 15 min later during 'on with or without dyskinesias', depending on two doses of levodopa. The transition from the 'off' to the 'on' state, with a complete reversal of parkinsonism, was characterized by a decrease (most cells), no changes or an increase in the firing rate of individual GPi cells. During dyskinesias firing rates fell profoundly in almost all cells, with decrements as low as 97% in individual cells. These changes occurred only when dyskinesias were present. The difference in GPi activity between 'on' and